EFFECT OF CIMETIDINE ON LIPID PEROXIDATION IN THE LUNGS OF PREMATURE NEWBORN INFANTS. † 1956

Cimetidine reduces acute hyperoxic lung injury in lambs. Injury reduction appears to be due to inhibition of P450 activity in lung and a consequent decrease in release of free-radical oxidants by isoforms of this enzyme system that are induced by increased O₂ tension (JAP 67:2486, 1989; JCI 96:2083, 1995). To determine whether cimetidine might have a similar beneficial effect in newborn premature infants at risk for bronchopulmonary dysplasia, we used a mass spectrometic assay to measure F₂-isoprostane levels in tracheobronchial aspirate fluid (TBAF) before and after giving a 24-hour i.v. infusion of cimetidine (0.5 mg/kg/h) to 6 NICU patients receiving mechanical ventilation. F₂-isoprostanes (F₂I) are free-radical catalyzed metabolites of arachidonic acid which are produced independent of cyclooxygenase and which have been shown to be a highly sensitive and specific marker of lipid peroxidation in vivo. Study patients had a birth weight of 1170 ±468 g, and were 88 ±42 h postnatal age and receiving an FIO₂ of 0.43 ±0.15 when the cimetidine infusion began. Five of the 6 patients had detectable F₂I in TBAF before cimetidine. F₂I levels decreased significantly in all 5 of these patients from 33 (18-405) pg/mL (median, range) to 17 (0-100) (P=0.043, Wilcoxon signed ranks test) without a significant change in FIO₂ (P=0.686). The average decrease following cimetidine was 58 ±35% of baseline. The patient with the lowest detectable F₂I level had the smallest decrease (8%). Since cimetidine is not known to have intrinsic anti-oxidant properties, these results support the hypothesis that P450 is a significant source of free-radical oxidants in the lungs of premature newborn infants and that blockade of P450 with cimetidine will reduce oxidant-induced lung injury.

(Supported by NIH Pediatric Pulmonary SCOR HL-14214)